Cigarette smoking is the chief preventable cause of morbidity and mortality in the US and is the leading preventable cause of cancer. Healthcare settings provide enormous potential for reaching smokers and delivering effective smoking treatments. Yet, too few smokers receive smoking treatments in these settings and the treatments they receive are not sufficiently effective. This Program Project aims to address these gaps by developing and implementing both an electronic health record (EHR) system that increases smokers' recruitment into treatment and a highly effective chronic care treatment with intervention components for all smokers. First, a new EHR system will be implemented in 18 clinics in 3 healthcare systems and experimentally evaluated on its ability to increase the recruitment of smokers into chronic care treatment (Project 1). Then, using highly efficient research methods, we will experimentally compare multiple intervention components that, when combined, will produce an optimized treatment package that addresses all phases of the smoking treatment process. The package will: increase quitting motivation among smokers initially unwilling to quit and prepare them for cessation (Project 2), enhance quitting success and prevent relapse when smokers are ready to quit (Project 3), and re-engage smokers in treatment and restore their abstinence if they have relapsed (Project 4). Our highly integrated research projects, supported by four cores, will thus implement a powerful new EHR strategy to efficiently recruit primary care patients who smoke into chronic care treatment for smoking. Our team has unique strengths in: smoking cessation treatment research in healthcare settings, established collaborations with EHR vendors and primary care clinics, comparative effectiveness research, and research methods. Project integration is fostered by a shared EHR-based recruitment platform, overlapping samples across projects as participant's transition through phases of the cessation process, and use of common measures across projects. Conducting this work in real-world clinics increases its potential for real-world application. The results of this Program Project will advance both research methods and the successful treatment of smoking in healthcare settings.